Thymoquinone/harmaline and related reaction products

ABSTRACT

New compositions of matter useful for the treatment of human diabetes and cancers comprise the reaction products of thymoquinone and harmaline or harmaline-like compounds, such as β-carboline compounds, and the derivatives, solvates, prodrugs, isomers, and tautomers of such compounds.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of U.S. patent applicationSer. No. 16/380,279 filed Apr. 10, 2019, which claims the benefit of twoU.S. Provisional Applications, Ser. 62/798,547 filed Jan. 30, 2019 andSer. 62/657,315 filed Apr. 13, 2018; each of the above-referencedapplications is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION Field of the Invention

The present invention relates to thymoquinone (TQ) adducts withharmaline and related compounds, which are useful for the treatment ofhuman cancers and diabetes, and corresponding methods for the treatmentof human suffering from cancers or other maladies. The inventionprovides dosage forms for administration to human patients, and methodsof formulating and administering such dosage forms to yield improvementsin treatment outcomes.

Description of the Prior Art

Diabetes is a disease that occurs when a patient's blood glucose (alsocalled blood sugar) is too high. Blood glucose is main source of energyand is derived from ingested food. Insulin, a hormone made by thepancreas, assists in the absorption of blood glucose by cells, where itis used as an energy source. Patients suffering from diabetes do notmake enough insulin, or do not use insulin well. Over time, bloodglucose can cause severe health problems, such as heart disease, stroke,kidney disease, eye problems, dental disease, nerve damage, and problemswith the extremities. Type I diabetes occurs when the body does not makeinsulin, and is usually diagnosed in children and young adults. Peoplewith Type I diabetes need to take insulin to survive. Type II diabetesoccurs when the body does not make or use insulin well. This type ofdiabetes can occur at any age, but most often is seen in middle-aged andolder people. Type II diabetes is the most common version. Diabetes istreated with lifestyle changes, including diet and exercise regimes.Additionally, a wide variety of diabetes drugs have been developed andare widely used.

Cancer is a generic term for a large group of diseases that can affectany part of the body. Other terms used are malignant tumors andneoplasms. One defining feature of cancer is the rapid creation ofabnormal cells that grow beyond their usual boundaries, and which canthen invade adjoining parts of the body and spread to other organs. Thisprocess is referred to as metastasis. Metastases are the major cause ofdeath from cancer.

The transformation from a normal cell into a tumor cell is a multistageprocess, typically a progression from a pre-cancerous lesion tomalignant tumors. These changes are the result of the interactionbetween a person's genetic factors and three categories of externalagents, including:

-   -   physical carcinogens, such as ultraviolet and ionizing radiation    -   chemical carcinogens, such as asbestos, components of tobacco        smoke, aflatoxin (a food contaminant) and arsenic (a drinking        water contaminant)    -   biological carcinogens, such as infections from certain viruses,        bacteria or parasites.

Some examples of infections associated with certain cancers:

-   -   Viruses: hepatitis B and liver cancer, Human Papilloma Virus        (HPV) and cervical cancer, and human immunodeficiency virus        (HIV) and Kaposi sarcoma.    -   Bacteria: Helicobacter pylori and stomach cancer.    -   Parasites: schistosomiasis and bladder cancer.

Aging is another fundamental factor for the development of cancer. Theincidence of cancer rises dramatically with age, most likely due to abuildup of risks for specific cancers that increase with age. Theoverall risk accumulation is combined with the tendency for cellularrepair mechanisms to be less effective as a person grows older.

Tobacco use, alcohol use, low fruit and vegetable intake, and chronicinfections from hepatitis B (HBV), hepatitis C virus (HCV) and sometypes of Human Papilloma Virus (HPV) are leading risk factors for cancerin low- and middle-income countries. Cervical cancer, which is caused byHPV, is a leading cause of cancer death among women in low-incomecountries. In high-income countries, tobacco use, alcohol use, and beingoverweight or obese are major risk factors for cancer.

The most common cancer treatment modalities are surgery, chemotherapy,and radiation treatments. All of these techniques have significantdrawbacks in terms of side effects and patient discomfort. For example,chemotherapy may result in significant decreases in white blood cellcount (neutropenia), red blood cell count (anemia), and platelet count(thrombocytopenia). This can result in pain, diarrhea, constipation,mouth sores, hair loss, nausea, and vomiting.

Biological therapy (sometimes called immunotherapy, biotherapy, orbiological response modifier therapy) is a relatively new addition tothe family of cancer treatments. Biological therapies use the body'simmune system, either directly or indirectly, to fight cancer or tolessen the side effects that may be caused by some cancer treatments.

During chemotherapies involving multiple-drug treatments, adverse drugevents are common, and indeed toxicities related to drug-druginteractions are one of the leading causes of hospitalizations in theUS. Obach, R. S. “Drug-Drug Interactions: An Important NegativeAttribute in Drugs.” Drugs Today 39.5 (2003): 301-338. In fact, in anysingle-month period, one-fifth of all surveyed adults in the USAreported an adverse drug response. Hakkarainen, K. M. et al. “Prevalenceand Perceived Preventability of Self-Reported Adverse Drug Events—APopulation-Based Survey of 7,099 Adults.” PLoS One 8.9 (2013): e73166. Alarge-scale study of adults aged 57-85 found that 29% were taking morethan five prescription medications and nearly 5% were at risk of majoradverse drug-drug interactions. In the field of oncology, a review ofover 400 cancer patients determined that 77% were taking drugs that wereconsidered to have a moderately severe potential for adverse druginteractions, and 9% had major adverse drug interactions. Mani, S. etal. “Alterations of Chemotherapeutic Pharmocokinetic Profiles byDrug-Drug Interactions.” Expert Opin. Drug Metabl. Toxicol 5.2 (2009):109-130.

Such interactions are a global health problem, and the WHO hasdetermined that negative drug interactions are leading causes ofmorbidity and mortality around the world, with up to 7% of allhospitalizations in the US due to negative drug interactions. A recentsurvey of a single hospital shows that 83% of hospitalized patients wereprescribed drug combinations with the potential to cause adversereactions. Patel, P. S. et al. “A Study of Potential Adverse Drug-DrugInteractions Among Prescribed Drugs in a Medicine Outpatient Departmentof a Tertiary Care Teaching Hospital.” J. Basic Clin. Pharm. 5.2 (2014):44-48.

TQ is a phytochemical compound found in the plant Nigella sativa, and isalso found in select cultivated Monarda fistulosa plants grown and steamdistilled. TQ has been used as a medicinal agent, such as ananti-convulsant in pediatric epilepsy, as an anti-inflammatory agent,and as an antioxidant. Additionally, TQ has been investigated foranti-cancer effects against several cancer cell lines and animal models.See, e.g., AbuKhader, M. M. “Thymoquinone in the Clinical Treatment ofCancer: Fact or Fiction?” Pharmacogn Review. 2013 July-December7(14):117-120. Additionally, TQ conjugates with terpenes and fatty acidshave also been proposed. Further references include U.S. Pat. Nos.6,218,434, 8,3931,959, 8,586,629, 8,802,161, 8,841,264, 9,180,155, and9,404,130; US Patent Publication No. 2016/0213727; and non-patentreference, Khader et al, “Thymoquinone: an emerging natural drug with awide range of medical applications,” Iran J Basic Med Sci 2014;17:950-957.

SUMMARY OF THE INVENTION

The present invention provides compositions which may be used asimproved chemotherapeutics for treatment of humans, and especially fortreatment of human cancers and diabetes, and corresponding methods forpreparing such compositions and use thereof. Generally speaking, thechemotherapeutics of the invention are in the form of reaction productsof TQ with harmaline and related compounds, and the derivatives,solvates, prodrugs, isomers, and tautomers thereof. The reactionproducts can be directly used, or can be modified or derivatized toprovide therapeutically effective and pharmaceutically acceptableesters, metal complexes (e.g., Cu, Fe, Zn, Pt, V), and salts.

Thymoquinone, C10H12O2, is identified as CAS #490-91-5, and has amolecular weight of 164.2. It has the structure

Harmaline (7-methoxy-1-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole) is afluorescent psychoactive alkaloid from the group of harmala alkaloidsand β-carbolines, and occurs in various plants, such as Peganum harmala.Harmaline is identified as CAS #304-21-2, and exists in two tautomericforms:

As used herein, “harmaline” refers to either or both tautomers.

In another aspect of the invention, compounds related to or similar toharmaline may be used to form the TQ reaction products of the invention.

The invention also provides new methods for treatment of cancers anddiabetes (both Type I and Type II) by administration of appropriatequantities of the reaction product compositions hereof. Hence, thecompositions are particularly designed for use in the treatment ofcancers and diabetes, and the compositions can be used for themanufacture of medicaments for anti-cancer and anti-diabetes therapeuticapplications. In addition, the invention provides compositions for thetreatment of cancers and diabetes comprising administeringtherapeutically effective amounts of the new compositions, prepared byprocesses known per se, with a pharmaceutically acceptable carrier.

A “chemotherapeutic,” “chemotherapeutic agent,” or simply “therapeuticagent,” as used herein refers to one or more of the reaction products ofTQ and harmaline described herein as useful in the treatment of humanconditions, especially human cancers and diabetes. Chemotherapeutics maybe cytostatic, selectively toxic or destructive of cancerous tissueand/or cells, including cancer stem cells, but also includeindiscriminately cytotoxic compounds used in cancer treatments.

A study of the reaction products of the invention reveals that certainof the products are isomers and have a molecular weight of approximately378, or, in dehydrated forms, about 360. Still further, other reactionproducts have molecular weights of about 542 and, in oxidized forms,about 540. All molecular weights referred to herein are approximate,meaning that the listed molecular weights are +/−5 weight units. Also,the molecular weights of the reaction product derivatives (e.g.,reduction products produced by hydrogenation, esters, or salts) would besomewhat different; such weights are easily calculated in light of thenature of the derivatives. Hence, the preferred molecular weightsrecited herein are for the non-derivatized versions of the reactionproducts.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph illustrating the body weight effect of a reactionproduct in accordance with the invention, as set forth in Example 2;

FIG. 2 is a graph illustrating the blood glucose effect of a reactionproduct in accordance with the invention, as set forth in Example 2;

FIG. 3 is a graph illustrating cell cytotoxicity results using onecompound in accordance with the invention, as set forth in Example 4;

FIG. 4 is a graph illustrating cell cytotoxicity results using anothercompound in accordance with the invention, as set forth in Example 4;

FIG. 5 is a graph illustrating baseline insulin secretion assay resultswith varying amounts of glucose alone and in conjunction with DMSO, asset forth in Example 5;

FIG. 6 is a graph illustrating insulin secretion assay results withvarying amounts of glucose and diazoxide, as set forth in Example 5;

FIG. 7 is a graph illustrating insulin secretion assay results withvarying amounts of compound C1 with 2 mM glucose, as set forth inExample 5;

FIG. 8 is a graph illustrating insulin secretion assay results with 10mM glucose and varying amounts of compound C1, as set forth in Example5;

FIG. 9 is a graph illustrating insulin secretion assay results with 20mM glucose and varying amounts of compound C1, as set forth in Example5;

FIG. 10 is a graph illustrating insulin secretion assay results with 2mM glucose and varying amounts of compound C2, as set forth in Example5;

FIG. 11 is a graph illustrating insulin secretion assay results with 10mM glucose and varying amounts of compound C2, as set forth in Example5;

FIG. 12 is a graph illustrating insulin secretion assay results with 20mM glucose and varying amounts of compound C2, as set forth in Example5;

FIG. 13 is a graph illustrating insulin secretion assay results withvarying amounts of glucose, with and without 100 nM gliclazide, as setforth in Example 6;

FIG. 14 is a graph illustrating insulin secretion assay results with 2mM glucose and varying amounts of compound C3, as set forth in Example6;

FIG. 15 is a graph illustrating insulin secretion assay results with 10mM glucose and varying amounts of compound C3, as set forth in Example6; and

FIG. 16 is a graph illustrating insulin secretion assay results with 20mM glucose and varying amounts of compound C3, as set forth in Example6.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The therapeutic agents of the invention are used in therapeuticallyeffective amounts, i.e., amounts that will elicit the biological ormedical response of a tissue, system, or subject that is being sought,and in particular to elicit some desired therapeutic effect against avariety of human diseases, and especially cancers and diabetes; in thecase of cancers, the agents operate by preventing and/or inhibitingproliferation and/or survival of cancerous cells, including cancer stemcells, and/or by slowing the progression of cancers. Those skilled inthe art recognize that an amount may be considered therapeuticallyeffective even if the condition is not totally eradicated or prevented,but it or its symptoms and/or effects are improved or alleviatedpartially in the subject. Of course, the appropriate makeup of theagents hereof and dosing regimens using such agents will depend on theparticular cancer or diabetes being treated, the extent of the disease,and other factors related to the patient as determined by those skilledin the art. Hence, the terms “therapeutic” or “treat,” as used herein,refer to products or processes in accordance with the invention that areintended to produce a beneficial change in an existing condition (e.g.,cancerous tissue, tumor size, metastases, etc., and the amelioration ofdiabetes symptoms) of a subject, such as by reducing the severity of theclinical symptoms and/or effects of the condition, and/or reducing theduration of the symptoms/effects of a subject.

Additional ingredients may be included with the chemotherapeutic agentsof the invention for administration to the subject. Such additionalingredients include, other active agents, preservatives, bufferingagents, salts, carriers, excipients, diluents, or otherpharmaceutically-acceptable ingredients. The active agents that could beincluded in the compositions include antiviral, antibiotic, or otheranticancer compounds; the latter could include the compounds describedin PCT publication serial number WO2016/064676, such as curcumin,harmine, and isovanillin, and metabolites, derivatives, isomers,tautomers, esters, complexes and salts of any of the foregoing.

The therapeutic agents of the invention give significant and unexpectedtherapeutic results, particularly in the context of anti-cancer andanti-diabetes results. In use, a therapeutically effective amount of anagent or composition in accordance with the invention is administered toa subject in need thereof. Such may comprise a single unit dosage or,more usually, periodic (e.g., daily) administration of lower dosagesover time.

The dosages may be administered in any convenient manner, such as byoral, rectal, nasal, ophthalmic, parenteral (including intraperitoneal,gastrointestinal, intrathecal, intravenous, cutaneous (e.g., dermalpatch), subcutaneous (e.g., injection or implant), or intramuscular)administrations. The dosage forms of the invention may be in the form ofliquids, gels, suspensions, solutions, or solids (e.g., tablets, pills,or capsules). Moreover, therapeutically effective amounts of the agentsof the invention may be co-administered with other chemotherapeuticagent(s), where the two products are administered substantiallysimultaneously or in any sequential manner.

Levels of dosing using the compositions of the invention are quitevariable owing to factors such as the patient's age, patient's physicalcondition, the type of condition(s) being treated (e.g., specificcancer(s) or diabetes), and the severity of the conditions. In general,however, regardless of the dosage form or route of administrationemployed, such as liquid solutions or suspensions, capsules, pills, ortablets, via oral, parenteral, or injection, the compositions should bedosed of from about 5 to 2000 mg per day, and more usually from about100-800 mg per day. Such dosages may be based on a single administrationper day, but more usually multiple administrations per day.

As used herein, the phrase “and/or,” when used in a list of two or moreitems, means that any one of the listed items can be employed by itselfor any combination of two or more of the listed items can be employed.For example, if a composition is described as containing or excludingcomponents A, B, and/or C, the composition can contain or exclude Aalone; B alone; C alone; A and B in combination; A and C in combination;B and C in combination; or A, B, and C in combination.

The present description also uses numerical ranges to quantify certainparameters relating to various embodiments of the invention. It shouldbe understood that when numerical ranges are provided, such ranges areto be construed as providing literal support for claim limitations thatonly recite the lower value of the range as well as claim limitationsthat only recite the upper value of the range. For example, a disclosednumerical range of about 10 to about 100 provides literal support for aclaim reciting “greater than about 10” (with no upper bounds) and aclaim reciting “less than about 100” (with no lower bounds).

As used herein, pharmaceutically acceptable salts with reference to thereaction products of the present invention mean salts of the reactionproducts which are pharmaceutically acceptable, i.e., salts which areuseful in preparing pharmaceutical compositions that are generally safe,non-toxic, and neither biologically nor otherwise undesirable and areacceptable for human pharmaceutical use, and which possess the desireddegree of pharmacological activity. Such pharmaceutically acceptablesalts include acid addition salts formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or with organic acids such as1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,2-naphthalenesulfonic acid, 3-phenylpropionic acid,4,4′-methylenebis(3-hydroxy-2-ene-1-carboxylic acid),4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, acetic acid,aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acids,aromatic sulfuric acids, benzenesulfonic acid, benzoic acid,camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid,cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid,glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid,heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid,laurylsulfuric acid, maleic acid, malic acid, malonic acid, mandelicacid, methanesulfonic acid, muconic acid, o-(4-hydroxybenzoyl)benzoicacid, oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substitutedalkanoic acids, propionic acid, p-toluenesulfonic acid, pyruvic acid,salicylic acid, stearic acid, succinic acid, tartaric acid,tertiarybutylacetic acid, trimethylacetic acid, and the like.Pharmaceutically acceptable salts also include base addition salts whichmay be formed when acidic protons present are capable of reacting withinorganic or organic bases. Acceptable inorganic bases include sodiumhydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide andcalcium hydroxide. Acceptable organic bases include ethanolamine,diethanolamine, triethanolamine, tromethamine, N-methylglucamine and thelike. It should be recognized that the particular anion or cationforming a part of any salt of this invention is not critical, so long asthe salt, as a whole, is pharmacologically acceptable. Additionalexamples of pharmaceutically acceptable salts and their methods ofpreparation and use are presented in Handbook of Pharmaceutical SaltsProperties, and Use, P. H. Stahl & C. G. Wermuth eds., ISBN978-3-90639-058-1 (2008).

In preparing the reaction product compositions of the invention, useshould be made of ingredients of relatively high purity, typically atleast about 90% by weight pure, and more preferably at least about 98%by weight pure. The use of naturally occurring sources for theingredients is generally not appropriate or desirable, because thesenaturally occurring products contain relatively small amounts of thedesired components and/or have potentially interfering compoundstherein. Use of low-purity ingredients often leads to little or noreaction products in accordance with the invention.

Thus, the preferred starting compounds or components of the inventionare either synthetically derived or derived from one or more naturallyoccurring product(s) which have been significantly modified so as tocontain at least about 90% by weight (more preferably at least about 98%by weight) of the desired component. As used herein, “syntheticallyderived” means that the component in question was synthesized usingspecific starting ingredients and one or more chemical and/or biologicalreactions to obtain substantially pure compounds. Modification ofnaturally occurring products may involve extractions, or any otherphysical or chemical steps to achieve the desired end product.

One technique for preparing the TQ-harmaline reaction products is to mixtogether solid particulate TQ and harmaline or a similar harmaline-likecompound, followed by the addition of a non-interfering solvent,especially organic solvents such as ethanol, or a 90% ethanol/10%dimethyl sulfoxide (DMSO) mixture to the particulates, and allowing themixture to stand for 24 hours at room temperature. More broadly, theweight ratio of TQ:harmaline should range from about 0.5:1 to 25:1, morepreferably from about 0.7:1 to 6:1, and most preferably from about 1.5:1to 3:1. The most preferred weight ratio is 2:1. In terms of weightamounts, the amount of TQ should range from about 25-95% by weight, andthe weight of amount of harmaline should be from about 5-75% by weight,with the total weight of these ingredients taken as 100% by weight. Inmost cases, however, it is preferred that the amount of TQ be present ina weight excess relative to the amount of harmaline or like compound.

As noted, the TQ and harmaline or a harmaline-like compound are usuallymixed with an organic solvent, such as a C1-C4 lower alcohol (e.g.,ethanol) and/or DMSO, and allowed to stand for a period (typically fromabout 12 hours-4 weeks) at a temperature ranging from about 20-60° C.The amount of solvent is quite variable and can range from about 10-100mg/mL.

The production of effective esters, metal complexes, andpharmaceutically acceptable salts is quite straightforward and wellwithin the skill of the art. For example, salts may be formed byreaction with inorganic or organic acids.

TQ/Harmaline Reaction Products

An analysis of the reaction products reveals that some productsdescribed below have molecular weights of about 378, and which may existin equilibrium with dehydrated versions having molecular weights ofabout 360 (all molecular weights reported herein were derived usingconventional liquid chromatography/mass spectrometry techniques).Structures I-VII below illustrate various forms of these reactionproducts, where Structures I-IV are isomers, and Structure VII is adehydrated version of Structure VI.

The above reaction products are characterized by a single thymoquinonemoiety and a single harmaline or harmaline-like moiety. Thesepredominate during the initial stages of the reactions. In thesereactions, the substituent of the pyridyl ring of harmaline reacts at anunsubstituted carbon atom which is alpha to either of the carbonylgroups of TQ. This phenomenon is illustrated in Structures I-IV above.In another reaction scheme, the substituent of the pyridyl ring ofharmaline reacts directly with either of the carbonyl groups of TQ.These types of reactions are illustrated in Structures V-VII above.

The thermodynamic properties of the harmaline and TQ reactants andreaction products I-IV isomers (MW 378) were used to obtain reactionenergetics using Density Functional Theory (DFT). Additionalcalculations were used to determine enthalpy, entropy, and Gibbs freeenergy values for the reactions. Reaction products II and IV were foundto be the most thermodynamically favorable and smaller free energyvalues. Reaction product II was deemed to be the most stable and had thelowest free energy value. Note that compounds II and IV arecharacterized by reaction of the pyridyl ring methyl substituent withone of the two unsubstituted carbon atoms alpha to a correspondingcarbonyl carbon, and two hydroxyl substituents on the TQ ring.

However, if the reaction mixtures are allowed to set for an extendedperiod of time, e.g., from about 3-30 days, other reaction productshaving higher molecular weights of about 542, or in oxidized forms,about 540 are formed as the predominant reaction product. These reactionproducts are characterized by the presence of two thymoquinone moietiesand a single harmaline or harmaline-like moiety. These same types ofhigher molecular weight species can be obtained if, after the initialreaction to yield the 378/360 MW products I-VII, the reaction mixturesare refluxed for a period of from about 30-120 minutes.

In particular, the MW 542 reaction products, and their oxidized MW 540reaction products, formed by the reaction between thymoquinone andharmaline are set forth below as compounds VIIIA-VIIIF:

Presently, compounds II and IV above are deemed to be the most active,particularly in the context of diabetes.

Related Harmaline Reactants

Certain similar or related harmaline compounds can be used in theproduction of the TQ reaction products of the invention, in lieu of orin combination with harmaline. Suitable “harmaline-like” compounds areβ-carbolines, and especially compounds of the structure

where the right-hand, numbered 6-member fused ring is heterocyclic witha single N atom at any of the positions 2-5, the R6 and R7 substituentsmay be located at any ring position, and R6 is H or C1-C4 alkoxy (morepreferably a C1-C2 alkoxy), and R7 is H, a C1-C4 alkyl (more preferablya C1-C2 alkyl), or a C1-C4 carboxylic acid (more preferably a C1-C2carboxylic acid).

Representative compounds of this type include harmaline and thefollowing:

The methods of preparing the reaction products using the compounds ofStructure IX are the same as those applicable to the preferredTQ/harmaline reaction products. In like manner, the weight ratios of TQto the Structure IX compounds are the same as those described above inconnection with TQ and harmaline, as are the levels of dosing and thetypes of dosage forms which may be prepared.

Thus, the weight ratio of TQ to the Structure IX compounds in thereaction mixtures should range from about 0.5:1 to 25:1, more preferablyfrom about 0.7:1 to 6:1, and most preferably from about 1.5:1 to 3:1.The most preferred weight ratio of TQ:Structure IX compound(s) is 2:1.In terms of weight amounts, the TQ amount should range from about 25-95%by weight, and the weight of amount of Structure IX compound(s) shouldbe from about 5-75% by weight, with the total weight of these reactantstaken as 100% by weight. In most cases, it is preferred that the weightamount of TQ should be present in a weight excess relative to the amountof the Structure IX compound(s).

The TQ and Structure IX compound(s) are usually mixed with an organicsolvent, such as a C1-C4 lower alcohol (e.g., ethanol) and/or dimethylsulfoxide (DMSO), and allowed to stand for a period (typically fromabout 12 hours-4 weeks) at a temperature ranging from about 20-60° C.The most preferred conditions are the addition of organic solvent at alevel of from about 10-100 mg/mL, with standing for 24 hours at roomtemperature.

The production of effective esters, metal complexes, andpharmaceutically acceptable salts of the TQ/Structure IX compounds, aswell as all other compounds within the ambit of the invention, is quitestraightforward and well within the skill of the art. For example, saltsmay be formed by reaction with inorganic or organic acids, as previouslydescribed.

Certain preferred reaction products in accordance with the invention areset forth in Structures X and XI below, where Structure X corresponds tothe lower MW products and Structure XI corresponds to the higher MWproducts.

where the six-membered A ring in each of the above structures is eitherphenyl or cyclohexadiene, the R1-R5 substituents may be attached at anyvalence-permitted position around the corresponding A rings, R1 is aC1-C4 alkyl group, R2 is H or a C1-C4 alkyl group, R3 and R4 areindependently either —OH or ═O, R5 is isopropyl, and the dotted bondline refers to the fact that the bond between the 1 position on the Aring and the intermediate CH2 or CH group of the linker between the Aring and the six-membered, N-containing pyridyl ring may be either asingle bond or a double bond. In structure XI, the A rings may be thesame or different.

EXAMPLES Example 1

A. Objective/Rationale

This test was designed to evaluate the in vivo activity of theTQ-harmaline reaction product (referred to as “TQ 725”), which was amixture of compounds I-IV and VI (MW about 378), V and VII (MW about360), and VIIID and VIIIF (MW about 540), as single agent in the NODmouse model of diabetes. Subsequent investigations have confirmed thatcompounds VI and VII are the most active. The female NOD mice showevidence of diabetes onset by age week 12 and 70% presenting withdiabetes (non-fasting plasma glucose higher than 250 mg/dl) by age week20. The significant endpoint is assessment of weekly blood glucoselevels.

B. Materials and Methods

1. Test System

Species/strain: NOD/ShiLtJ (Stock No: 001976) Physiological state:Diabetic Age/weight range at time 8-11 weeks (NOD/ShiLtJ) - 11 weeks ofreceipt: preferred if offered by the vendor Number/sex of animals:40/Female* Replacement: Animals were not replaced during the course ofthe study. *Number of mice were reduced to 36 prior to study starting.

2. Animal Housing and Environment

Housing: Individually ventilated microisolator cages Acclimation: Atleast 5-7 days Environmental conditions: Maintained under pathogen-freeconditions Food/water: Ad libitum, Teklad Global Diet ® 2920x irradiatedpellets, autoclaved water.

3. Test Article—TQ 725.

Physical description: Solid taffy Storage conditions: 4° C. protectedfrom light

4. Test Article/Vehicle Mixture—TQ 725

Dosage forms: Suspension Dosage preparation/storage: Suspension of TZ725 in 10% dimethyl acetamide (DMA) + 90% polyethylene glycol(PEG400)/4° C. protected from light Stability/expiration date: Preparedfresh prior to dosing

5. Administration of Test Agent—TQ 725

Route and method of administration: Oral Administration per os (PO)Frequency and duration of dosing: Daily to end (QD to end) Administereddoses: 100 mg/kg, 200 mg/kg, 400 mg/kg, and 600 mg/kg Administeredvolume(s): 10 mL/kg

6. Standard Agent—Metformin

Identity: Metformin Physical description: Solid Storage conditions: Roomtemperature away from light and moisture Stability/expiration date:Greater than study duration

7. Standard Agent/Vehicle Mixture—Metformin

Dosage form: Solution Dosage preparation/storage: Aqueous solutionStability/expiration date: Aqueous solutions were stable for theduration of the study, kept at 4° C.

8. Administration of Standard Agent—Metformin

Route and method of Oral Administration (PO) administration: Frequencyand duration of dosing: Ad libitum, days 1-8 in drinking water; oralgavage daily, days 9-56 Administered doses: 600 mg/kg

9. Vehicle Control

Identity: 10% DMA + 90% PEG400

10. Vehicle Mixture—Vehicle Control

Dosage form: solution Dosage preparation/storage: 10% DMA + 90% PEG400

11. Administration of Vehicle Control

Route and method of administration: Oral Administration (PO)Administered doses:  0 mg/kg Administered volume(s): 10 mL/kg

12. Experimental Design

Study initiation: At approximately 23 weeks of age, mice were randomizedinto treatment groups (Day 0) for baseline blood glucose measurements.Randomization method: Random equilibration of glucose levels and bodyweights Treatment initiation: On Day 1, According to Table 1 below. DataCollection: Body Weights two times weekly; Gross observations daily(negative observations will be recorded) Study Endpoint(s): 8 Weeks PostStudy Initiation

13. Tissue Collection

In-study collections: Pre-dose; then once weekly for 8 weeks prior todosing animals Moribund mice will have blood glucose collections priorto sacrifice when possible Tissue: Blood Glucose Collection Method: Tailprick Group(s): All Groups Preservation Method: N/A Samples per All MiceAnalysis Method: Glucose Meter group:

14. Daily Dosing Schedule

TABLE 1 Study Groupings Group N* Dosing Schedule 1. Vehicle Control (PO)6 10 ml/kg 2. TQ 725(PO) 6 100 mg/kg days 1-27 400 mg/kg days 28-37 600mg/kg days 38-56 3. TQ 725 (PO) 5 200 mg/kg days 1-56 4. Metformin (PO)6 Ad libitim days 1-8 600 mg/kg days 9-56 *Number of mice in group.

The pancreatic tissues from the test mice were assayed by conventionalinsulin staining according to the following ratings: 0—no staining onislet cells; 1—of islets with positive stains, stain cells are minimalin number; 2—of islets with positive stain, stain cells are less than50% of the cells; 3—of the islets with positive stains, stain cells aregreater than 50% of the cells.

The staining data showed a mean value of 0.67 for Group 1, 1.5 for Group2, 2.40 for Group 3, and 0.50 for Group 4. Thus, the data demonstrated amarked increase insulin staining for the TQ 725 Groups 2 and 3, ascompared with the control Group 1 and the Metformin Group 4.

The collected body weight data for the test mice indicated that theMetformin Group 4 weights trended downwardly, whereas the body weightsof the Group 3 mice were almost always higher than those of Group 4. Thebody weight data was not deemed to be a reliable parameter since micewere sacrificed and removed during the course of the test, whicheffected body weight results.

FIGS. 1 and 2 illustrate the body weight and blood glucose level resultscollected during the test. In each of these Figures, graph A refers toGroup 1, the vehicle control (PO) QD to end; graph B refers to Group 2,725.001 100 mg/kg days 1-27, followed by 400 mg/kg days 28 to end (PO);graph C refers to Group 3, 725.001 200 mg/kg (PO) QD to end; and graph Drefers to Group 4, metformin 600 mg/kg (in H2O) Ad libitum days 1-8,followed by 600 mg/kg (PO) QD days 9 to end.

The Group 3 graph C data was the most significant, in that itillustrated a general decline in blood glucose over the course of thestudy, with enhanced body weights. The Group 2 graph B data illustratedthat the increase in TQ 725 dosage during the course of the test loweredthe glucose levels. At about 35 days, the glucose levels of the Group 3graph C mice fell below those of the Group 4 graph D mice, and thistrend continued throughout the remainder of the test.

Example 2

The purpose of this study was to assess the maximum tolerated singledose of the TQ 725 product as a single agent in 27 femalenon-tumor-bearing SCID beige mice. A stepwise approach was used todetermine the single dose tolerability.

The mice were five weeks of age at the time of dosing and had a normalphysiological state. The mice were housed in individual, ventilated,microisolator cages under pathogen-free conditions. The mice were fed Adlibitum Teklad Global Diet 2920× eradiated pellets, and autoclavedwater. IACUC Protocol #16094 was followed.

The test product was a DMSO solution containing 100 mg/mL of the TQ 725reaction product stored at 4° C. and protected from light. This testproduct was used to prepare a dosage form made up of 10% of the DMSO/725test product, diluted with 90% PEG 400 by gentle hand mixing. The dosageform was stored at 4° C. and protected from light.

The dosage form was administered orally in a single dose. Three groupsof 9 mice each acclimated at 7, 8, and 9 days, respectively, were givendoses of 50 mg/kg, 75 mg/kg, and 100 mg/kg. One mouse per group wasdosed and observed. When no acute tolerability-related adverse clinicalsigns were noted, the remaining mice of each group were dosed.

The mice were observed over a period of 10 days and daily data of bodyweight and gross observations were collected. There was only mild bodyweight loss and no significant tolerability-related clinicalobservations or death. Therefore, it was concluded that the product waswell-tolerated at all of the dose levels tested.

Example 3

In this Example, in vitro cell proliferation assays were performedusing: (1) Human Myeloma tumor cell lines; (2) Human Lymphoma tumor celllines; (3) Solid Human tumor cell lines; and (4) Parental, Lenalidomideresistant and Bortezomib resistant Jeko-1 Mantle cell Lymphoma tumorcell lines. The reaction product tested was the TQ 725 product describedabove.

Each proliferation assay was carried out as follows. The test cells wereplated in growth media using a 384-well microtiter plate at 50 μLvolume. The cells were incubated for 24 hours at 37° C. in a humidifiedincubator. After 24 hours of incubation, the test TQ 725 product wasadded to the test wells in DSMO solvent, at a concentration ranging of10.5 mM. Control wells received equal volumes of DSMO, without thereaction product. Following drugging, the cells were incubated for 72hours at 37° C. in a humidified incubator. After this exposure, 100 μLof a 1:1 mixture of sterile water and CellTiter-Glo® reagent (Promega)was added to each well. The plates were then incubated for 60 minutes atroom temperature, followed by recording the luminescence value of eachwell using a luminometer as a measure of cell proliferation.

The following Table sets forth a summary of the IC₅₀ Results.

In Vitro Cell Proliferation Assay Summary of IC₅₀ Results Mean IC₅₀ (μM)Cell Line Tissue Type TQ 725 MIA PaCa-2 Pancreatic 8.983 ASPC-1 11.62BxPC-3 10.56 AN3CA Endometrial 8.226 HEC-1a 18.01 MDA-MB-231 TNBC 5.270MDA-MB-468 5.540 HCC70 18.99 H1975 (EGFR mut) NSCLC 7.100 H1650 (EGFRmut) 14.29 A2780 Ovarian 2.237 A2780CP 4.717 RXF-393 RCC 6.022 A49813.85 N87 Gastric 9.604 SiHA Squamous Cell 40.99 FaDu 14.43 DOHH-2 DLBCL4.232 SU-DHL-4 1.168 SU-DHL-6 0.7158 OCI-LY3 0.9209 JIM1 human myeloma8.197 KHM-1B 4.377 KMM-1 6.118 KMS-11 15.85 KMS-27 7.256 KMS-34 16.91H929 14.19 L363 12.65 MM.1S 4.795 MOLP-8 1.746 Jeko-1 Parental MantleCell Lymphoma 4.378 Jeko-1 8.917 Lenalidomide Resistant Jeko-1 5.705Bortezomib Resistant

Example 4

In this example, two of the compounds in accordance with the invention,referred to as C1 and C2, were identically tested to determine cellcytotoxicities. C1 has a molecular weight of about 378 and is a mixtureof compounds I-IV and VI. C2 has molecular weight of about 360 and is amixture of compounds V and VII. The cell line used was MIN-6 (ATCCCRL-11506) pancreatic beta cells. The cells were seeded into 96-wellplates (10⁴ cells/well) along with Dulbecco's Modified Eagle Medium(DMEM) containing 10% fetal bovine serum, 0.05 mM 2-mercaptoethanol, 100U/mL penicillin, 100 μg/mL streptomycin, 3.7 g/L NaHCO3, 25 mM glucose,and 200 mM glutamine, with incubation under a humidified atmosphere at37° C. with 5% C02. After 72 hours of incubation, the cells were treatedwith compounds C1 and C2, respectively, in 0.5% DMSO at levels of 0.1,1.0, 10, and 100 μg/mL, and allowed to react overnight. Thereupon, eachwell was treated with 20 μL of freshly prepared (5 mg/mL) MTT(3-(4,5-dimethylthizol-2-yl)-2,5-diphenyltetrazolium bromide) stock in1×PBS, followed by an additional hour of incubation. Finally, 100 μL ofDMSO was added to each well, and the absorbance was recorded at 570 nm.A control was identically prepared and tested, except that the cellswere not treated with either test compound. A positive control of methylmethanesulphonate (1000 μM) was also tested.

FIGS. 3 and 4 illustrate the results from this test where the data ispresented as % cell viability compared to the cell control. Asindicated, compound C1 was not toxic to the MIN-6 cells at tested doses.In the case of compound C2, no toxicity was observed at lowerconcentrations, but significant cell cytotoxicity towards the MIN-6cells was visible at 100 μg/mL.

Example 5

In this test, a glucose stimulated insulin secretion assay was performedusing the MIN-6 cell line and compounds C1 and C2 of Example 4. The testdetails and assay conditions are set forth below.

A. Test Details

Cell Line MIN-6 Cell Density 3 × 10⁴ cells/well Compounds C1 C2Diazoxide Solvent DMSO Test Concentrations 1.0, 10.0 μg/mL Cell ControlKrebs Ringer Buffer (KRB) containing 0.1% BSA (no glucose) VehicleControl 0.5% DMSO Control Glucose + 0.5% DMSO Test Glucose + C1 or C2 inDMSO

B. Assay Conditions

The cells were washed with KRB containing 0.1% BSA and starved for 1hour in 2 mM glucose-KRB/BSA at 37° C. in 5% CO2. Following starvation,the cells were treated with or without the compounds at varying glucoseconcentrations of 2 mM, 10, mM, and 20 mM in KRB/BSA for 1 hour at 37°C. in 5% CO2. The amount of secreted mouse insulin was measured in theKRB/BSA incubation buffer using the mouse insulin ELISA kit from MercerEXPert Assays. The cells were then lysed for protein quantification. Thedata presented in FIGS. 5-6 illustrate the secreted insulin test resultsfor glucose and diazoxide, while FIGS. 7-9 (compound C1) and 10-12(compound C2) illustrate the secreted insulin test results using C1 andC2. The data presented in FIGS. 7-12 are presented as the fold changesin the secreted insulin per milligram protein per hour, compared to thecell control.

C. Results

Concentration-dependent insulin secretion is evident upon varying theconcentration of glucose with MIN-6 cells. The test compounds wereevaluated at different glucose concentrations and the results showedthat both compounds C1 and C2 enhanced glucose-mediated insulinsecretion.

Compound C1 led to an increase of 146-228% insulin secretion. Thepercentage increase was higher in the range of 2-10 nM. Compound C2showed an increase of 165-267% insulin secretion. The percentageincrease was higher at the higher concentration of glucose. Diazoxideshowed significant inhibition of insulin secretion.

Example 6

In this test, a glucose stimulated insulin secretion assay was performedusing the MIN-6 cell line and a compound mixture of compounds VIIID andVIIIF (MW about 540), referred to as C3. The test details and assayconditions are set forth below.

A. Test Details

Cell Line MIN-6 Cell Density 3 × 10⁴ cells/well Compounds C3 GliclazideSolvent DMSO Test Concentrations 0.185, 1.85, and 18.5 μM Gliclazide:100 nM Cell Control Krebs Ringer Buffer (KRB) containing 0.1% BSA (noglucose) Vehicle Control 0.5% DMSO Control Glucose + 0.5% DMSO TestGlucose + C3 in DMSO

B. Assay Conditions

The cells were washed with KRB containing 0.1% BSA and starved for 1hour in 2 mM glucose-KRB/BSA at 37° C. in 5% CO2. Following starvation,the cells were treated with or without the compounds at varying glucoseconcentrations of 2 mM, 10, mM, and 20 mM in KRB/BSA for 1 hour at 37°C. in 5% CO2. The amount of secreted mouse insulin was measured in theKRB/BSA incubation buffer using the mouse insulin ELISA kit from MercerEXPert Assays. The cells were then lysed for protein quantification. Thedata is presented in FIGS. 13 (gliclazide) and 14-16 (C3) as the foldchange in the secreted insulin per milligram protein per hour, comparedto the cell control.

As reflected in the graphical data of FIGS. 13-16, insulin secretion isshown using varying concentrations of glucose in MIN-6 cells. Gliclazidewas used as a positive control, and exhibited enhanced insulin secretionat 10 mM of glucose. Moreover, C3 enhanced glucose-mediated insulinsecretion in the range of 2-10 mM of glucose and further exhibited anoticeable increase of 1.58-3.18 folds in insulin secretion. Thepercentage increase was highest at 2 mM glucose. C3 gave the bestresults in the concentration range of 0.185-1.85 μM.

Example 7

In this test, another glucose stimulated insulin secretion assay wasperformed using two test compounds, namely C1 (MW about 378) and C3 (MWabout 540). The MIN-6 cell line was used and the test details and assayconditions are set forth below.

A. Test Details

Cell Line MIN-6 Cell Density 10⁴ cells/well Compounds C1 C3 GliclazideSolvent DMSO Test Concentrations 0.264, 2.64, and 26.4 μM Gliclazide:100 μM Cell Control Krebs Ringer Buffer (KRB) (no glucose) VehicleControl 0.5% DMSO Control Glucose 2 mM and 25 mM + 0.5% DMSO TestGlucose 2 mM and 25 mM + C1 and C3 in DMSO

B. Assay Conditions

The cells were revived and maintained in T-flasks. Upon reaching therequired confluency, the cells were seeded in 96-well plates. The seededcells were serum-starved in the presence of glucose for 30 minutes at37° C. in 5% CO2. Following starvation, the cells were treated with orwithout the compounds at the varying glucose concentrations in KRB for 2hours at 37° C. in 5% CO2. The cell supernatants were collected andtested for insulin secretion using the mouse insulin ELISA kit fromMercer EXPert Assays.

Insulin secretion was enhanced by glucose stimulation. In the presenceof Gliclazide (100 μM), the enhanced insulin secretion was observed atthe lower glucose concentration. At the higher glucose concentration,Gliclazide showed a saturation effect. The C1 compound demonstratedincreased insulin secretion as compared with the glucose control, with asaturation effect at the higher glucose level. The C3 compound exhibitednegligible enhancement of insulin secretion at all three dosage levels.

As reflected in the graphical data of FIGS. 13-16, insulin secretion isshown using varying concentrations of glucose in MIN-6 cells. Gliclazidewas used as a positive control, and exhibited enhanced insulin secretionat 10 mM of glucose. Moreover, C3 enhanced glucose-mediated insulinsecretion in the range of 2-10 mM of glucose and further exhibited anoticeable increase of 1.58-3.18 folds in insulin secretion. Thepercentage increase was highest at 2 mM glucose. C3 gave the bestresults in the concentration range of 0.185-1.85 μM.

While the anti-cancer properties of the compositions of the inventionhave been demonstrated against certain cancers, it is considered thatthe invention is applicable to virtually all cancers, such as thefollowing: Acute Lymphoblastic Leukemia, Adult; Acute LymphoblasticLeukemia, Childhood; Acute Myeloid Leukemia, Adult; Acute MyeloidLeukemia, Childhood; Adrenocortical Carcinoma; Adrenocortical Carcinoma,Childhood; Adolescents, Cancer in; AIDS-Related Cancers; AIDS-RelatedLymphoma; Anal Cancer; Appendix Cancer; Astrocytomas, Childhood;Atypical Teratoid/Rhabdoid Tumor, Childhood, Central Nervous System;Basal Cell Carcinoma; Bile Duct Cancer, Extrahepatic; Bladder Cancer;Bladder Cancer, Childhood; Bone Cancer, Osteosarcoma and MalignantFibrous Histiocytoma; Brain Stem Glioma, Childhood; Brain Tumor, Adult;Brain Tumor, Brain Stem Glioma, Childhood; Brain Tumor, Central NervousSystem Atypical Teratoid/Rhabdoid Tumor, Childhood; Brain Tumor, CentralNervous System Embryonal Tumors, Childhood; Brain Tumor, Astrocytomas,Childhood; Brain Tumor, Craniopharyngioma, Childhood; Brain Tumor,Ependymoblastoma, Childhood; Brain Tumor, Ependymoma, Childhood; BrainTumor, Medulloblastoma, Childhood; Brain Tumor, Medulloepithelioma,Childhood; Brain Tumor, Pineal Parenchymal Tumors of IntermediateDifferentiation, Childhood; Brain Tumor, Supratentorial PrimitiveNeuroectodermal Tumors and Pineoblastoma, Childhood; Brain and SpinalCord Tumors, Childhood (Other); Breast Cancer; Breast Cancer andPregnancy; Breast Cancer, Childhood; Breast Cancer, Male; BronchialTumors, Childhood; Burkitt Lymphoma; Carcinoid Tumor, Childhood;Carcinoid Tumor, Gastrointestinal; Carcinoma of Unknown Primary; CentralNervous System Atypical Teratoid/Rhabdoid Tumor, Childhood; CentralNervous System Embryonal Tumors, Childhood; Central Nervous System (CNS)Lymphoma, Primary; Cervical Cancer; Cervical Cancer, Childhood;Childhood Cancers; Chordoma, Childhood; Chronic Lymphocytic Leukemia;Chronic Myelogenous Leukemia; Chronic Myeloproliferative Disorders;Colon Cancer; Colorectal Cancer, Childhood; Craniopharyngioma,Childhood; Cutaneous T-Cell Lymphoma; Embryonal Tumors, Central NervousSystem, Childhood; Endometrial Cancer; Ependymoblastoma, Childhood;Ependymoma, Childhood; Esophageal Cancer; Esophageal Cancer, Childhood;Esthesioneuroblastoma, Childhood; Ewing Sarcoma Family of Tumors;Extracranial Germ Cell Tumor, Childhood; Extragonadal Germ Cell Tumor;Extrahepatic Bile Duct Cancer; Eye Cancer, Intraocular Melanoma; EyeCancer, Retinoblastoma; Gallbladder Cancer; Gastric (Stomach) Cancer;Gastric (Stomach) Cancer, Childhood; Gastrointestinal Carcinoid Tumor;Gastrointestinal Stromal Tumor (GIST); Gastrointestinal Stromal CellTumor, Childhood; Germ Cell Tumor, Extracranial, Childhood; Germ CellTumor, Extragonadal; Germ Cell Tumor, Ovarian; Gestational TrophoblasticTumor; Glioma, Adult; Glioma, Childhood Brain Stem; Hairy Cell Leukemia;Head and Neck Cancer; Heart Cancer, Childhood; Hepatocellular (Liver)Cancer, Adult (Primary); Hepatocellular (Liver) Cancer, Childhood(Primary); Histiocytosis, Langerhans Cell; Hodgkin Lymphoma, Adult;Hodgkin Lymphoma, Childhood; Hypopharyngeal Cancer; IntraocularMelanoma; Islet Cell Tumors (Endocrine Pancreas); Kaposi Sarcoma; Kidney(Renal Cell) Cancer; Kidney Cancer, Childhood; Langerhans CellHistiocytosis; Laryngeal Cancer; Laryngeal Cancer, Childhood; Leukemia,Acute Lymphoblastic, Adult; Leukemia, Acute Lymphoblastic, Childhood;Leukemia, Acute Myeloid, Adult; Leukemia, Acute Myeloid, Childhood;Leukemia, Chronic Lymphocytic; Leukemia, Chronic Myelogenous; Leukemia,Hairy Cell; Lip and Oral Cavity Cancer; Liver Cancer, Adult (Primary);Liver Cancer, Childhood (Primary); Lung Cancer, Non-Small Cell; LungCancer, Small Cell; Lymphoma, AIDS-Related; Lymphoma, Burkitt; Lymphoma,Cutaneous T-Cell; Lymphoma, Hodgkin, Adult; Lymphoma, Hodgkin,Childhood; Lymphoma, Non-Hodgkin, Adult; Lymphoma, Non-Hodgkin,Childhood; Lymphoma, Primary Central Nervous System (CNS);Macroglobulinemia, Waldenström; Malignant Fibrous Histiocytoma of Boneand Osteosarcoma; Medulloblastoma, Childhood; Medulloepithelioma,Childhood; Melanoma; Melanoma, Intraocular (Eye); Merkel Cell Carcinoma;Mesothelioma, Adult Malignant; Mesothelioma, Childhood; MetastaticSquamous Neck Cancer with Occult Primary; Mouth Cancer; MultipleEndocrine Neoplasia Syndromes, Childhood; Multiple Myeloma/Plasma CellNeoplasm; Mycosis Fungoides; Myelodysplastic Syndromes;Myelodysplastic/Myeloproliferative Neoplasms; Myelogenous Leukemia,Chronic; Myeloid Leukemia, Adult Acute; Myeloid Leukemia, ChildhoodAcute; Myeloma, Multiple; Myeloproliferative Disorders, Chronic; NasalCavity and Paranasal Sinus Cancer; Nasopharyngeal Cancer; NasopharyngealCancer, Childhood; Neuroblastoma; Non-Hodgkin Lymphoma, Adult;Non-Hodgkin Lymphoma, Childhood; Non-Small Cell Lung Cancer; OralCancer, Childhood; Oral Cavity Cancer, Lip and; Oropharyngeal Cancer;Osteosarcoma and Malignant Fibrous Histiocytoma of Bone; Ovarian Cancer,Childhood; Ovarian Epithelial Cancer; Ovarian Germ Cell Tumor; OvarianLow Malignant Potential Tumor; Pancreatic Cancer; Pancreatic Cancer,Childhood; Pancreatic Cancer, Islet Cell Tumors; Papillomatosis,Childhood; Paranasal Sinus and Nasal Cavity Cancer; Parathyroid Cancer;Penile Cancer; Pharyngeal Cancer; Pineal Parenchymal Tumors ofIntermediate Differentiation, Childhood; Pineoblastoma andSupratentorial Primitive Neuroectodermal Tumors, Childhood; PituitaryTumor; Plasma Cell Neoplasm/Multiple Myeloma; Pleuropulmonary Blastoma,Childhood; Pregnancy and Breast Cancer; Primary Central Nervous System(CNS) Lymphoma; Prostate Cancer; Rectal Cancer; Renal Cell (Kidney)Cancer; Renal Pelvis and Ureter, Transitional Cell Cancer; RespiratoryTract Cancer with Chromosome 15 Changes; Retinoblastoma;Rhabdomyosarcoma, Childhood; Salivary Gland Cancer; Salivary GlandCancer, Childhood; Sarcoma, Ewing Sarcoma Family of Tumors; Sarcoma,Kaposi; Sarcoma, Soft Tissue, Adult; Sarcoma, Soft Tissue, Childhood;Sarcoma, Uterine; Sezary Syndrome; Skin Cancer (Nonmelanoma); SkinCancer, Childhood; Skin Cancer (Melanoma); Skin Carcinoma, Merkel Cell;Small Cell Lung Cancer; Small Intestine Cancer; Soft Tissue Sarcoma,Adult; Soft Tissue Sarcoma, Childhood; Squamous Cell Carcinoma; SquamousNeck Cancer with Occult Primary, Metastatic; Stomach (Gastric) Cancer;Stomach (Gastric) Cancer, Childhood; Supratentorial PrimitiveNeuroectodermal Tumors, Childhood; T-Cell Lymphoma, Cutaneous;Testicular Cancer; Testicular Cancer, Childhood; Throat Cancer; Thymomaand Thymic Carcinoma; Thymoma and Thymic Carcinoma, Childhood; ThyroidCancer; Thyroid Cancer, Childhood; Transitional Cell Cancer of the RenalPelvis and Ureter; Trophoblastic Tumor, Gestational; Unknown PrimarySite, Carcinoma of, Adult; Unknown Primary Site, Cancer of, Childhood;Unusual Cancers of Childhood; Ureter and Renal Pelvis, Transitional CellCancer; Urethral Cancer; Uterine Cancer, Endometrial; Uterine Sarcoma;Vaginal Cancer; Vaginal Cancer, Childhood; Vulvar Cancer; WaldenströmMacroglobulinemia; Wilms Tumor; Women's Cancers.

We claim:
 1. A method of treating a subject to decrease the bloodglucose level of the subject, comprising the step of administering tothe subject one or more compounds of Structures X and XI below, and thederivatives, solvates, prodrugs, isomers, tautomers, esters, metalcomplexes, and salts thereof:

where the six-membered A ring in each of the above structures is eitherphenyl or cyclohexadiene, the R1-R5 substituents may be attached at anyvalence-permitted position around the corresponding A rings, R1 is aC1-C4 alkyl group, R2 is H or a C1-C4 alkyl group, R3 and R4 areindependently either —OH or ═O, R5 is isopropyl, and the dotted bondline refers to the fact that the bond between the 1 position on the Aring and the intermediate CH2 or CH group of the linker between the Aring and the six-membered, N-containing pyridyl ring may be either asingle bond or a double bond, and in structure XI, the A rings may bethe same or different.
 2. The method of claim 1, the one or morecompounds of Structure X having a molecular weight of about
 378. 3. Themethod of claim 1, the one or more compounds of Structure XI having amolecular weight of about
 540. 4. The method of claim 1, the one or morecompounds of Structure X having the R3 and R4 substituents both being—OH.
 5. The method of claim 1, said R3 and R4 —OH substituents beinglocated at A ring positions 3 and 6, respectively.
 6. The method ofclaim 1, the one or more compounds of Structure X having said R2substituent being methyl.
 7. The method of claim 6, the compounds ofStructure X having an R2 methyl substituent located either at A ringpositions 2 or 5, and an R5 isopropyl substituent located at the otherof said A ring positions 2 or
 5. 8. The method of claim 1, said A ringseach being phenyl.
 9. The method of claim 1, said administered compoundbeing of the Structure


10. The method of claim 1, said administered compound being of theStructure